The similarity of simian immunodeficiency virus (SIV) to human immunodeficiency virus (HIV) in genomic organization, genetic sequence and biological properties suggests that SIV systems are highly suitable for study of the mechanisms and determinants of HIV-induced disease. The research described in this application examines molecular determinants of SIV persistence and AIDS pathogenesis. These studies utilize molecularly cloned SIV of defined sequence that has been shown to cause AIDS in rhesus monkeys. Specifically, cloned SIVs with alterations in the nef gene and in the NRE (negative regulatory element) will be tested for their properties in cultured cells and in rhesus monkeys. The role of the nef gene and the NRE in viral persistence, pathogenic potential, cell specificity and disease course will be analyzed. A requirement of nef or NRE for viral persistence and/or pathogenic potential will have important implications for therapy and vacine research. If nef is required for the pathogenic potential of the virus, the nef gene product will become an important target for drug development.